Idiopathic pulmonary fibrosis (IPF) is a deadly lung disease that affects an estimated 133,000 patients in the U.S. and more than 5 million worldwide. Median survival time after diagnosis is only 2-3 years, with a 5-year mortality rate exceeding 50%. IPF is the leading indication for lung transplant in most large treatment centers. The hallmark of the disease is progressive and ultimately fatal scarring in the lungs, detectable with high resolution computed tomography (HRCT) and lung biopsy. There is no consistent standard of care, and there are no FDA-approved agents to prevent, arrest, or reverse fibrosis. Consequently, a tremendous unmet need persists for the development of a truly disease-modifying drug for this indication. The goal of this phase I SBIR preclinical research program is to identify such an agent for IPF, which can then be further advanced for clinical evaluation in affected patients. The approach is based on increasing recognition of the role of a particular subset of cell surface molecules called 'integrins' as key regulators of the activity of the predominant cytokine, TGF , that is known to drive fibrosis progression. The innovative technologies employed in this application involve: 1) a series of small drug molecules that are unique in that they potently and simultaneously antagonize the function of the entire subset of known TGF -activating integrins, and 2) direct delivery of the compounds to the primary site of pathology in the lungs via inhaled aerosol formulations. Preliminary studies with a representative antagonist of this compound series have already demonstrated efficacy in experimental murine models of both lung and liver fibrosis with systemic delivery. Furthermore, our recent studies have shown that delivery of this compound to mouse lungs using a microsprayer suppressed TGF signaling in lung macrophages for at least 12 hours. We also showed that daily pulmonary drug delivery nearly completely blocked the development of bleomycin-induced lung fibrosis. We now propose to explore aerosol formulations with other existing test compounds to optimize biophysical parameters for lung penetration and retention, and then administer the formulation directly to the lungs of rats to evaluate pharmacokinetics and pharmacodynamic responses. This research has the potential to rapidly lead to human clinical trials and provide an effective approach to modify the course of a devastating disease for which there is currently no effective treatment.